Skin-penetrating peptides (SKPs) are emerging as a promising class of permeation enhancers that can facilitate macromolecule delivery across the skin. Although their pharmaceutical applications are under extensive study, SKPs are crucial for enhancing skin permeability, enabling larger molecules to penetrate the stratum corneum. This review explores the transformative role of SKPs in non-invasive transdermal drug delivery. Drawing from an extensive collection of literature, it provides insights into the current usage and application of SKPs as tools to enhance skin permeability and facilitate the delivery of larger molecules. Additionally, it highlights the opportunities, challenges, and future directions for SKP applications in transdermal drug delivery.